鉴定纯能受体的碳水化合物识别基因的鉴定
Lifen Zhao1, Fangyu Wei1,2, Xinheng He1,2
1State Key Laboratory of Drug Research, Carbohydrate-Based Drug Research Center and National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
eLife
|November 13, 2023
概括
研究人员发现了碳水化合物如何激活G蛋白合受体 (GPCRs),特别是P2Y14. 确定了一个保存的盐桥基因 (KDKE),区分不同的糖核酸,并为碳水化合物药物开发提供了洞察力.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 碳水化合物是参与许多生物过程的必不可少的生物分子.
- 碳水化合物调节药物点的精确机制,如G蛋白合受体 (GPCRs),尚未完全理解.
- P2Y纯感受体14 (P2Y14) 是一种涉及炎症和免疫反应的GPCR,使其成为一个相关的药物标.
研究的目的:
- 研究糖核酸对GPCRs的激活机制.
- 为了确定尿素二酸盐 (UDP) - 糖与P2Y14受体的特定结合部位和相互作用.
- 探索保存基因在区分不同UDP糖的作用及其在药物开发中的潜在应用.
主要方法:
- 利用分子动力学模拟来建模受体-连接体相互作用.
- 综合计算发现与功能研究,以验证结合点和激活机制.
- 采用位点定向突变发生法来识别参与糖结合的关键氨基酸残留物.
主要成果:
- 确定了P2Y14上的尿素二酸盐 (UDP) -糖结合部位.
- 揭示了UDP-葡萄糖通过桥梁跨膜螺旋2和7来激活P2Y14.
- 发现了一种保存的盐桥链 (K2.60-D2.64-K7.35-E7.36 [KDKE]) 负责区分各种UDP糖.
- 确定了KDKE链作为P2Y14和P2Y12受体中糖结合的保存功能动机.
- 设计了新的UDP-糖类类似物作为P2Y12的激动剂,证明了治疗潜力.
结论:
- 阐明了一种新的糖核酸激活GPCRs的机制,特别是P2Y14.
- 突出了KDKE基因在UDP糖识别和受体激活中的关键作用.
- 为合理设计以碳水化合物为基础的药物提供了宝贵的见解,这些药物针对炎症和免疫疾病的纯能受体.
相关概念视频
G Protein-coupled Receptors
12.2K
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
12.2K
Transducer Mechanism: G Protein–Coupled Receptors
2.0K
G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
GPCRs are also called heptahelical,...
2.0K
GPCR Desensitization
6.1K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
6.1K
GPCRs Regulate Adenylyl Cylase Activity
5.6K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.6K
G-protein Coupled Receptors
119.9K
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
119.9K
Transducer Mechanism: Enzyme-Linked Receptors
2.5K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.5K


